Process for preparation of aromatic and heteroaromatic molecules

Abstract

A process for the attachment of aromatic or heteroaromatic rings to a polymeric support via a silyl ether linkage is described. Such process involves the synthesis of a chlorodialkyl aryl or heteroarylsilane which is then coupled to a polymeric support via a hydroxyl functionality to form a polymer-bound silyl ether. Further modification provides a polymer-bound small organic molecule that is cleaved from the polymeric support under mild conditions to give an aryl or heteroaryl silanol or a compound in which the aryl or heteroaryl carbon-silicon bond is replaced with a carbon-hydrogen, carbon-halogen, carbon-hydroxyl, carbon-sulfur, or carbon-carbon bond. Such methods are useful for the preparation of a library of diverse aromatic and heteroaromatic compounds by both manual and automated synthesis.

What is claimed is:  
     
       1. A process for preparing pharmaceuticals or agrochemicals comprising: 
       a) An aryllithium or heteroaryllithium reagent is first reacted with a substituted or unsubstituted dichlorosilane forming a silicon-carbon bond;  
       b) The resulting aryl-chlorosilane is reacted in one or more synthetic steps with a solid-supported hydroxyl group to form a silicon-oxygen bond (silyl ether) which thereby links the aromatic or heteroaromatic synthon to the solid support;  
       c) The solid-supported aromatic or heteroaromatic synthon is reacted, in one or more synthetic steps, to form a solid-supported molecules which, when detached from the support, afford pharmaceuticals or agrochemicals.  
     
     
       2. A process according to claim  1  wherein the dichlorosilane is symmetrically substituted by two identical lower alkyl groups of 1-6 carbon atoms which are straight chain, branched or cyclic. 
     
     
       3. A process according to claim  1  wherein the dichlorosilane is unsymmetrically substituted by a phenyl ring and an alkyl group or by two different lower alkyl groups of 1 to 6 carbon atoms which are straight chain, branched or cyclic. 
     
     
       4. A process according to claim  1  wherein the aryllithium is a phenyl, a 1-naphthyl or a 2-naphthyl ring which is unsubstituted or substituted by 2-5 groups selected from the group consisting of: HO, H 2 N, SH, F, Br, Cl, CH 3 , CHO, CH 2 OH, CO 2 H, CN, CF 3 , CCl 3 , NO 2 , phenyl, OR, NHR, NR 2 , SR, C(═O)NHR, C(═O)OR, C(═O)R, SO 2 NHR, and SO 2 R or a suitably protected version thereof, wherein R is a straight or branched chain of eight or fewer carbon atoms that is unsubstituted or substituted by one or two functional groups selected from the group consisting of: OH, NH 2 , OCH 3 , CO 2 H, CO 2 CH 3 , CONH 2 ,                    
       and CN and may contain one or two carbon—carbon double bonds. 
     
     
       5. A process according to claim  1  wherein the heteroaryllithium is a 5- or 6-membered aromatic ring or a benzo-fused 5- or 6-membered aromatic ring system containing at least one N, O, or S atom which is unsubstituted or substituted by 2-5 groups selected from the group consisting of: HO, H 2 N, SH, F, Br, Cl, CH 3 , CHO, CH 2 OH, CO 2 H, CN, CF 3 , CCl 3 , NO 2 , phenyl, OR, NHR, NR 2 , SR, C(═O)NHR, C(═O)OR, C(═O)R, SO 2 NHR, and SO 2 R or a suitably protected version thereof, wherein R is a straight or branched chain of eight or fewer carbon atoms that is unsubstituted or substituted by one or two functional groups selected from the group consisting of: OH, NH 2 , OCH 3 , CO 2 H, CO 2 CH 3 , CONH 2 ,                    
       and CN and may contain one or two carbon—carbon double bonds. 
     
     
       6. A process according to claim  1  wherein the aryl-chlorosilane is reacted in one step by treatment with a base and a solid-supported hydroxyl group to generate a silyl-ether linkage. 
     
     
       7. A process according to claim  1  wherein the aryl-chlorosilane is first converted to an aryl-hydroxysilane and then activated by treatment with diethylazodicarboxylate and triphenylphosphine before reacting with a solid-supported hydroxyl group to generate a silyl-ether linkage. 
     
     
       8. A process according to claim  1  wherein the aryl-chlorosilane is first converted to an aryl-triflate and then reacted with a base and a solid-supported hydroxyl group to generate a silyl-ether linkage. 
     
     
       9. A process according to claim  1  wherein the solid-supported hydroxyl group is a hydroxyl group of hydroxymethyl polystyrene, p-benzyloxybenzyl alcohol resin, ethyleneglycol 2-chlorotrityl resin, 4-hydroxymethylbenzoic acid BHA resin, 4-hydroxymethylbenzoic acid MBHA resin or polyethyleneglycol-polystyrene composite polymer. 
     
     
       10. A process according to claim  1  wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n X(CH 2 ) m -polystyrene wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O); n is an integer from 1 to 6 and m is zero or one. 
     
     
       11. A process according to claim  1  wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n X-polyethyleneglycol-polystyrene composite polymer wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O) and n is an integer from 1 to 6. 
     
     
       12. A process according to claim  1  wherein the solid-supported hydroxylgroup is a hydroxyl group of HO(CH 2 ) n C(═O)—MBHA resin or HO(CH 2 ) n C(═O)—BHA resin and n is an integer from 1 to 6. 
     
     
       13. A process according to claim  1  wherein the solid-supported hydroxylgroup is a hydroxyl group of (4-hydroxyphenyl)—(CH 2 ) p X(CH 2 ) m -polystyrene wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O); p is an integer from 0 to 6 and m is zero or one. 
     
     
       14. A process according to claim  1  wherein the solid-supported hydroxylgroup is a hydroxyl group of (4-hydroxyphenyl)—(CH 2  ) p X-polyethyleneglycol-polys tyrene composite polymer wherein: X is O, S, C(═O)NH, NHC(═)O, N(Me)C(═O), C(═O)O, or OC(═O) and p is an integer from 0 to 6. 
     
     
       15. A process according to claim  1  wherein the carbon-silicon bond attaching the pharmaceutical or agrochemical to the solid support is cleaved by treatment with tetrabutylammonium fluoride or tris (dimethylamino) sulfonium difluorotrimethylsilicate in a polar-aprotic solvent or a mixture of polar-aprotic solvents at a temperature above 45° C. 
     
     
       16. A process according to claim  1  wherein the silicon-oxygen bond attaching the pharmaceutical or agrochemical to the solid support is cleaved by treatment with tetrabutylammonium fluoride in tetrahydrofuran, cesium fluoride in N,N-dimethylformamide, or trifluoroacetic acid in dichloromethane at less than 45° C. 
     
     
       17. A process according to claim  1  wherein the silicon-oxygen bond attaching the pharmaceutical or agrochemical to the solid-support is first cleaved according to claim  16  and then the silicon-carbon bond of the resulting silanol is cleaved by treatment with tetrabutylammonium fluoride or tris(dimethylamino)sulfonium difluorotrimethylsilicate in a polar-aprotic solvent or a mixture of polar-aprotic solvents at a temperature above 45° C. 
     
     
       18. A process according to claim  1  wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an oxygen-carbon bond in one or more steps by treatment with tetrabutylammonium fluoride and an oxidizing agent. 
     
     
       19. A process according to claim  1  wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an carbon—carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic carbon source. 
     
     
       20. A process according to claim  1  wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an sulfur-carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic sulfur source. 
     
     
       21. A process according to claim  1  wherein the silicon-carbon bond attaching the pharmaceutical or agrochemical to the solid support is converted to an halogen-carbon bond by treatment with tris(dimethylamino)sulfonium (trimethylsilyl)difluoride and an electrophilic halogen source. 
     
     
       22. A process according to claim  1  wherein a library of greater than twenty pharmaceuticals or agrochemicals bearing aromatic or heteroaromatic moieties are prepared via automated synthesis. 
     
     
       23. A process according to claim  1  wherein a library of greater than twenty pharmaceuticals or agrochemicals bearing aromatic or heteroaromatic moieties are prepared via manual synthesis. 
     
     
       24. A process according to claim  18  wherein the oxidizing agent is hydrogen peroxide, or peracetic acid. 
     
     
       25. A process according to claim  19  wherein the electrophilic carbon source is an aldehyde, an acid chloride, an alkyl halide, or an alkyl sulfonate. 
     
     
       26. A process according to claim  20  wherein the electrophilic sulfur source is a disulfide, a sulfinyl halide, a sulfonyl chloride, or an thiosulfonate. 
     
     
       27. A process according to claim  21  wherein the electrophilic halogen source is I 2 , Br 2 , Cl 2 , Icl, or tris(dimethylamino)sulfonium difluorotrimethylsilicate and N-halosuccinimides in DMF or another polar-aprotic solvent.